.alpha.-Conidendrin (ACON), podophyllotoxin (PT), and sikkimotoxin (ST), respective structures 1-3 of FIG. 1, are naturally occurring tetrahydronaphthalene lignans. PT and ST are isolated from roots and rhizomes of the genus Podophyllum. Also, PT is a product of plant cell culture. PT is known to inhibit nucleoside transport in mammalian cells and assembly of microtubles and has antiviral and antitumor activity, among other biological activities. For example, PT binds to tubulin, thereby inhibiting the assembly of tubulin into microtubules. This, in turn, results in the arrest of cell division at the mitotic stage of the cell cycle. Kelleher, Cancer Treat. Rep., 62: 1443 (1978)(Kelleher), reports a positive correlation between derivatives of PT and antineoplastic activity. In general, compounds which are strong inhibitors of microtubule assembly are believed to possess the strongest antitumor properties. However, because PT is highly toxic, it is not often used in medical applications.
Two semisynthetic derivatives of PT, teniposide and etoposide, respectfully shown as structures 4 and 5 in FIG. 2, are both effective in the treatment of a variety of leukemias and solid tumors. Although etoposide and teniposide are not inhibitors of microtubule assembly, they appear to exert their cytotoxic action through an interaction and inhibition of the enzyme tolpoisomerase II to cause increased single and double strand breaks in DNA. These and several other semisynthetic preparations from podophyllotoxin preserve the same carbo-oxygen, fused- and pendant-ring network possessed by podophyllotoxin. See U.S. Pat. No. 4,609,644 to Nemec.
Other derivative of podophyllotoxin have been produced. Ayers et al. J. Chem. Soc., 5025-5030 (1962), report an oxabicyclooctane derivative produced by acid-catalyzed dehydration of podophyllol, a triol reduction product of PT. Rodrigo, J. Org. Chem., 45(22): 4538-4540 (1980), reports an oxabicyclooctane prepared through acid catalyzed ether interchange in the course of a total synthesis of racemic podophyllotoxin. However, this intermediate was racemic as opposed to the optically active oxabicyclooctane derivatives of the present invention.
Structure-activity relationships studies indicate some structural features of PT and its derivatives influence their respective biological activity. Such structure-activity studies are reported by Letter et al., Cancer Res., 9: 625 (1949); Hartwell et al., J.Proc. Am. Assoc. Cancer Research, 2:19 (1954); Kelleher; Loike et al., Cancer Res., 38: 2688 (1978); Brewer et al., J. Med. Chem., 22: 215 (1979); and Tomioka et al., J. Med. Chem., 34: 54 (1991). Based upon these studies, the following general conclusions can be made: (a) a trans-fused relationship between C-9a and C-3a in ring D is important since the cis-fused derivatives exhibit greatly reduced or no biological activity, (b) the .alpha.-configuration of the pendant aryl ring (ring C) may be important for antitumor activity, but there is conflicting evidence on the importance of the configuration of the pendant aryl group, (c) the configuration of the hydroxyl group at C-9 has an effect on antitumor activity, but positioning of the hydroxyl group elsewhere in the molecule does not appear to have a marked effect on cytotoxic activity, (d) modification of the sugar moiety at C-9 in derivatives of PT can effect biological activity, and (e) conversion of the lactone ring of PT and deoxypodophyllotoxin (DPT) to a tetrahydrofuran ring diminishes inhibition of microtubule assembly by approximately 50%. Additionally, oxygenation at C-9 is required in etoposide and teniposide for the attachment of the glucopyranosyl unit.
ACON is an aryltetralin lignan found in sulfite waste liquor from pulping of the western hemlock. It is a white crystalline solid and occurs in two crystalline forms, one melting at approximately 255-256.degree. C. and the other melting at 238.degree. C. Although structurally similar to PT. it lacks the pendant aryl ring configuration present in many such cytotoxic, tetrahydronaphthalene lignans. Refluxing ACON with sodium methoxide in methanol results in the epimerization of the C-9a chiral center to give .beta.-conidendrin (BCON), shown in FIG. 3. BCON and picropodophyllotoxin are stereoisomers of ACON and podophyllotoxin, respectively, As an antitumor agent, ACON, BCON, and picropodophyllotoxin are biologically inactive.
A large number of derivatives of ACON and BCON have been synthesized. Most of these derivatives involve protection of --OH groups on rings A and D. As shown in FIG. 4, synthesized derivatives of ACON and BCON protect the --OH groups on rings A and D as a methoxy (19) and (23). Other synthesized derivatives of ACON protect the --OH groups on rings A and D as acetoxy, benzoyl, and toluenesulphonyl groups. Similarly, other synthesized derivatives of BCON protect the --OH groups on rings A and D as acetoxy and toluenesulfonyl groups. The tetraacetyl and terabenzoyl derivatives of .alpha.-conidendrol have also been synthesized. However, there is no known report on the selective protection of the --OH groups on rings A and D.
As shown in the reaction sequences of FIG. 4, other derivatives of ACON and BCON have been synthesized from dimethyl-.alpha.-conidendrin (19) and dimethl-.beta.-conidendryn (23). These derivatives are dimethyl-.alpha.-conidendryl alcohol (30), dimethyl-.beta.-conidendryl alcohol (31), dimethylanhydro-.alpha.-conidendryl alcohol (32), and dimethylanhydro-.beta.-conidendryl alcohol (33).
As can be seen, there are problems associated with the use of various naturally occurring tetrahydronaphthalene lignans as molecular source materials for cytotoxic agents. One such problem is the presence of an enolizable lactone; the second is an initial stereochemical configuration of the pendant aryl group inconsistent with achieving high cytotoxicity.
In view of the serious health effects of cancer, the need continues for compounds which exhibit cytotoxic effects on cancer cells. Further, there is a need for tetrahydronaphthalene lignans which can be utilized as a molecular source material for cytotoxic agents. Still, there is a need for derivative tetrahydronaphthalenes which possess a stereochemical configuration which provides high cytotoxicit. The present invention is directed to overcoming these deficiencies in the art.